(PQ12) Enhancement of DNA repair in neurons via a targeted APE1 small molecule modifier to decrease and reverse chemotherapy-induced peripheral neuropathy (CIPN)

(PQ12) 通过靶向 APE1 小分子修饰剂增强神经元 DNA 修复，以减少和逆转化疗引起的周围神经病变 (CIPN)

• 批准号: 10463843
• 负责人: JILL C FEHRENBACHER
• 金额: $ 45.16万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463843
• 关键词: Address; Advanced Development; Affect; Afferent Neurons; Animal Model; Antineoplastic Agents; Apoptosis; Attenuated; Base Excision Repairs; Behavior; Blood flow; Bone Marrow Neoplasms; Bone Marrow Suppression; Bone marrow failure; Carboplatin; Chemotherapy-induced peripheral neuropathy; Cisplatin; Clinical Trials; Colon; Coupled; DNA Damage; DNA Repair; DNA Repair Endonuclease; DNA Repair Enzymes; DNA Sequence Alteration; Data; Development; Dose; Effectiveness; Elements; Epothilones; Foundations; Future; Genetic; Genomics; Goals; Hair; Hepatitis C Therapy; Human; Immune; Immunomodulators; In Vitro; Interphase Cell; Japan; Knowledge; Limb structure; Liver Failure; Maintenance; Malignant Neoplasms; Measures; Mediating; Modeling; Morphology; Mus; Nausea; Nerve; Neuronal Dysfunction; Neurons; Neuropathy; Nociception; Numbness; Oxidation-Reduction; Pain; Pancreas; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase Ib/II Trial; Platinum; Platinum adduct; Prevention; Proprioception; Proteasome Inhibitor; Proteins; Quality of life; Safety; Sensory; Solid Neoplasm; Stress; Symptoms; Tendon Reflex; Testing; Therapeutic; Therapeutic Uses; Translating; Validation; Vinca Alkaloids; Work; allodynia; anti-cancer; anti-cancer therapeutic; anticancer activity; anticancer treatment; antitumor effect; base; cancer therapy; cell growth; chemotherapy; crosslink; drug candidate; effective therapy; efficacy testing; endonuclease; in vivo; in vivo Model; interest; mouse model; mutant; neoplastic cell; nephrotoxicity; nerve supply; neurotoxic; neurotoxicity; optimal treatments; oxaliplatin; oxidative DNA damage; phase 1 study; preclinical study; prevent; repair function; repaired; safety study; side effect; small molecule; taxane; treatment strategy; tumor

PROJECT SUMMARY/ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of many efficacious anticancer drugs, including platinum drugs, taxanes, proteasome inhibitors, vinca alkaloids, epothilones, and immunomodulators. Their neurotoxic side effects can be so debilitating that treatment may need to be reduced or stopped. However, unlike other major side effects of chemotherapy (e.g. nausea, hair loss, bone marrow failure), no standard, effective treatments exist to prevent or reverse CIPN. This is largely because the cellular mechanisms for CIPN have not been identified and the symptoms of CIPN including numbness, decreased blood flow to extremities, loss of proprioception, loss of tendon reflexes, pain, allodynia, and/or increased sensitivity to cold vary greatly in patients. Because CIPN is debilitating and may be irreversible, identification of key targets to prevent neurotoxicity without compromising the tumor-killing effects of anticancer drugs is critical in developing a first-in- class therapeutic that can directly affect a patient's ability to receive optimal treatment. Our previous studies examining the hypothesis that DNA damage of sensory neurons contributes to CIPN laid the foundation for the proposed work, which is poised to develop a drug candidate. We demonstrated that reducing DNA base excision repair (BER) activity by reducing expression of the apurinic/apyrimidinic endonuclease/redox factor (APE1) augmented the neurotoxicity produced by anticancer treatment, whereas supplementing APE1's repair activity attenuated the neurotoxicity. It is likely that, in non-dividing cells like neurons, DNA damage could alter the function of sensory neurons in ways that manifest as the symptoms observed in CIPN. Consequently, DNA repair would be critical for proper genetic expression of the right types and amounts of proteins, a crucial element of genomic maintenance. For the proposed studies, we will examine whether augmenting APE1 repair activity in vivo will prevent chemotherapy-induced alterations in sensory neuronal function (manifested as CIPN) without jeopardizing the cancer treatment. Using tumor bearing mice, we will examine whether a small molecule (E3330) which was identified to enhance APE1's DNA repair function in neurons can prevent (aim 1) or reverse (aim 2) DNA damage and alterations in the function of sensory neurons caused by cisplatin, oxaliplatin or carboplatin. Furthermore, we will examine whether the small molecule (E3330) will compromise the anticancer efficacy of the platinum drugs by examining DNA damage and tumor survival following treatment (aim 3). Because E3330 has been found to act as a single agent and in combination with other cancer therapeutic drugs to decrease tumor cell growth, this molecule has the potential to offer a “win-win” scenario; block tumor cell growth while protecting against neuronal dysfunction. Additionally, E3330 will enter a phase 1 clinical trial for solid tumors followed by phase 1b/phase 2 trials for various indications that include platinums in their SOC (e.g. colon, pancreatic). Therefore, it requires further preclinical study using an in vivo paradigm to demonstrate effectiveness in the context of neuronal protection and CIPN models.

项目概要/摘要 化疗引起的周围神经病变（CIPN）是许多有效抗癌药物的主要副作用， 包括铂类药物、紫杉烷类、蛋白酶体抑制剂、长春花生物碱、埃坡霉素和免疫调节剂。 它们的神经毒性副作用可能会使人衰弱，可能需要减少或停止治疗。 与化疗的其他主要副作用（例如恶心、脱发、骨髓衰竭）不同，没有标准， 存在预防或逆转 CIPN 的有效治疗方法，这主要是因为 CIPN 的细胞机制。 尚未确定，CIPN 的症状包括麻木、四肢血流减少、 本体感觉丧失、腱反射丧失、疼痛、异常性疼痛和/或对寒冷的敏感性增加在不同情况下差异很大 由于 CIPN 会使患者衰弱并且可能是不可逆转的，因此需要确定预防的关键目标。 在不影响抗癌药物的肿瘤杀伤作用的情况下消除神经毒性对于开发首创药物至关重要 类治疗可以直接影响患者接受最佳治疗的能力。 检验感觉神经元 DNA 损伤导致 CI​​PN 的假设奠定了基础 拟议的工作，准备开发一种候选药物，我们证明了减少 DNA 碱基切除。 通过减少无嘌呤/无嘧啶核酸内切酶/氧化还原因子 (APE1) 的表达来修复 (BER) 活性 增强抗癌治疗产生的神经毒性，同时补充 APE1 的修复活性 在神经元等非分裂细胞中，DNA 损伤可能会改变神经毒性。 感觉神经元的功能表现为 CIPN 测试中观察到的症状，DNA。 修复对于正确类型和数量的蛋白质的正确基因表达至关重要，这是一个关键因素 对于拟议的研究，我们将检查是否增强 APE1 修复。 体内活性将防止化疗引起的感觉神经元功能改变（已证实） 作为 CIPN），在不损害癌症治疗的情况下，我们将使用荷瘤小鼠来检查是否存在这种情况。 一种小分子（E3330）被鉴定可以增强神经元中 APE1 的 DNA 修复功能 预防（目标 1）或逆转（目标 2）引起的 DNA 损伤和感觉神经元功能的改变 此外，我们将检查是否是小分子（E3330）。 将通过检查 DNA 损伤和肿瘤来损害铂类药物的抗癌功效 治疗后的生存率（目标 3），因为 E3330 被发现可作为单一药物发挥作用。 与其他癌症治疗药物结合以减少肿瘤细胞的生长，该分子具有潜力 提供“双赢”的方案；阻止肿瘤细胞生长，同时防止神经元功能障碍。 E3330将进入实体瘤的1期临床试验，随后针对各种适应症进行1b期/2期试验 其 SOC 中包含铂（例如结肠、胰腺），因此需要使用进一步的临床前研究。 一种体内范例，用于证明神经保护和 CIPN 模型中的有效性。